This invention relates to the use of therapeutic agents in conjunction with the parenteral administration of lipid dispersions comprising colloidal suspensions of particulate lipids or particulate matter in association with lipid. It relates particularly to the use of therapeutic agents to reduce or eliminate the transient physiological stress reaction observed when fluorocarbon emulsions, emulsified lipids, and liposomal formulations are administered in vivo.
Fluorocarbon emulsions have many useful applications in medicine as intravascular and extravascular imaging or contrast agents. Also, the capacity of fluorocarbons to dissolve high concentrations of oxygen make them suitable as temporary red blood cell substitutes and as oxygen transport agents in the treatment of local ischemia. Frequently, however, the intravascular administration of fluorocarbon emulsions, and other agents comprising lipid dispersions, is accompanied by a mild transient systemic inflammatory and febrile response. The response is usually innocuous, and can be in many respects, beneficial; however, it can cause a period of discomfort for the recipient.
Several sources of physiological stress that occur during the administration of the lipid dispersions described, including the macrophage phagocytosis of particles, as well as the stress provoked by reduced oxygen tension, interrupted blood flow, or infection, can elicit a transient inflammatory response. The response is physiologically and biochemically mediated by the metabolic products of arachidonic acid, i.e., prostaglandins, thromboxane, and leukotrienes.
The biosynthesis of prostaglandins and thromboxane begins with the conversion of free arachidonic acid to an endoperoxide prostaglandin intermediate, PGH2, by means of a cyclooxygenase enzyme. PGH2 is then made available as the precursor for several end product prostanoids. Among these prostanoids are prostacyclin, PGI2, formation of which is catalyzed by prostacyclin synthetase; the active prostaglandins PGF2a. PGE2, and PGD; and the thromboxane, TxA2, the formation of which is catalyzed by thromboxane synthetase.
The prostaglandin and thromboxane end products have various effects on cells, but primarily act on macrophages and platelets to release other substances that in turn mediate an inflammatory response characterized by infiltration of the tissues with neutrophils, deposition of immune complexes, edema, and pain.
The prostanoids can have effects that oppose each other; for example, PGI2 and TxA2, the biologically most active of the prostanoids, exert opposite vasoactive and hemodynamic effects: PGI2 is a potent vasodilator and inhibitor of platelet aggregation, whereas TxA2 is a vasoconstrictor and promoter of platelet aggregation.
Various agents are known to inhibit or attenuate the biological activity of prostaglandins and thromboxane. Imidazole, a compound related to the naturally occurring amnino acid histidine, inhibits thromboxane synthetase and prevents the synthesis of TxA2; other agents, such as aspirin, ibuprofen, and indomethacin inhibit cyclooxygenase, thus preventing the synthesis of all the prostanoids.
Macrophage phagocytosis not only triggers the release of arachidonate metabolites, but also the release of cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor (TNF). These substances are known to elicit a febrile response via a mechanism of induced local release of prostaglandins in the hypothalamus of the brain. Corticosteroids, e.g., dexamethasone, can inhibit and down-regulate the release of cytokines from macrophages, and cyclooxygenase inhibitors, e.g., ibuprofen, can inhibit the formation of prostaglandins in the hypothalamus.
It would be advantageous to prevent the undesirable transient effects observed during the intravenous administration of lipid dispersions. Accordingly, it is an object of the invention to provide methods to prevent or ameliorate these effects by use of an agent which prevents a systemic inflammatory or febrile response by inhibiting the synthesis of prostaglandins, thromboxane and cytokines, or preventing their release from macrophages.
It is also an object of the invention to provide methods to prevent these adverse effects by the use of other agents which act to suppress an inflammatory or febrile response.
According to the invention there is provided a method for reducing the Transient Adverse Physiological Response (TAPR) in an animal to parenterally administered particulate dispersions, comprising the steps of administering an anti-inflammatory drug prophylactically to an animal in need thereof in an amount sufficient to oppose the TAPR response; and then administering said particulate dispersion parenterally to a patient. The method is an improvement over previous procedures of administering particulate dispersions, wherein the improvement comprises a prophylactic administration of an anti-inflammatory drug so as to prevent or ameliorate the symptoms of a transient adverse physiological reaction (TAPR) to the particulate dispersion which occasionally occurs, significantly in humans.
The particulate dispersion can comprise, for example, a dispersed lipid, fluorocarbon, or an emulsified triglyceride. The particulate dispersion can also be a liposomal formulation.
According to the method described, the prophylactic drug may be a corticosteroid; preferably the corticosteroid is dexamethasone or methylprednisone. Alternatively, the prophylactic anti-inflammatory drug is a cyclooxygenase inhibitor, a phospholipase A2 inhibitor, or an agent that otherwise inhibits the synthesis of prostaglandins and thromboxane. In one preferred embodiment, the cyclo-oxygenase inhibitor is chosen from the group consisting of indomethacin, ibuprofen, aspirin, and naproxen.
In the application of the method, the dose of the prophylactic anti-inflammatory drug is administered from 30 minutes to 24 hours prior to the procedure of injecting a particulate dispersion into an animal. The prophylactic drug can be administered in two or more doses. The method also comprises the further step of administering the prophylactic anti-inflammatory drug, either continuously or at intervals of time during and after the injection of a particulate dispersion into an animal.
The invention also includes fluorocarbon emulsions comprising an effective concentration of an agent that opposes the TAPR response, selected from the group consisting of steroidal and non-steroidal anti-inflammatory agents, antipyretic agents, and non-narcotic analgesics. The emulsion can, for example, comprise an effective TAPR-opposing amount of indomethacin, ibuprofen, naproxen, or combinations thereof. The anti-inflammatory agent can be aspirin, other salicylates, drugs having an imidazoyl group, or any of the non-steroidal anti-inflammatory agents of the various chemical classes disclosed herein. Alternatively, the emulsion can comprise an effective TAPR-opposing amount of a corticosteroid. In preferred embodiments, the corticosteroid can be dexamethasone or methylprednisone.